The present invention relates to methods and nutritional compositions for the prevention and treatment of cancer cachexia and anorexia. In the practice of the present invention patients are enterally administered xcfx89-3 fatty acids including, but not limited to alpha-linolenic (18:3 xcfx89-3), stearidonic (18:4 xcfx89-3), eicosapentaenoic (20:5 xcfx89-3) docosapentaenoic: (22:5 xcfx89-3), and docosahexaenoic (22:6 xcfx89-3), in combination with antioxidants including, but not limited to, beta-carotene, vitamin C, vitamin E, selenium, or mixtures thereof; a source of amino-nitrogen with high levels of branched-chain amino acids including valine, leucine, isoleucine, and with or without reduced levels of tryptophan and 5-hydroxytryptophan.
Cancer cachexia is a syndrome characterized by anorexia, weight loss, premature satiety, asthenia, loss of lean body mass, and multiple organ dysfunction. The majority of patients with cancer whose disease progresses to metastatic disease develop cachexia during their treatment program and the cachexia contributes to their deaths. The frequency of weight loss in cancer patients ranges from 40% for patients with breast cancer, acute myelocytic leukemia, and sarcoma to more than 80% in patients with carcinoma of the pancreas and stomach. About 60% of patients with carcinomas of the lung, colon or prostate have experienced weight loss prior to beginning chemotherapy. Although the relationship between pretreatment malnutrition (weightless) and adverse outcome is established, no consistent relationship has been demonstrated between the development of cachexia and tumor size, disease stage, and type or duration of the malignancy. Development of cachexia in the cancer patient is not caused simply by increased energy expenditure by the host or by the tumor. The malignant cachexia is partially related to reduced caloric intake.
Cancer cachexia is not simply a local effect of the tumor. Alterations in protein, fat, and carbohyrate metabolism occur commonly. For example, abnormalities in carbohydrate metabolism include increased rates of total glucose turnover, increased hepatic gluconeogenesis, glucose intolerance and elevated glucose levels. Increased lipolysis, increased free fatty acid and glycerol turnover, hyperlipidemia, and reduced lipoprotein lipase activity pre frequently noted. The weight loss associated with cancer cachexia is caused not only by a reduction in body fat stores but also by a reduction in total body protein mass, with extensive skeletal muscle wasting. Increased protein turnover and poorly regulated amino acid oxidation may also be important. Presence of host-derived factors produced in response to the cancer have been implicated as causative agents of cachexia, e.g., tumor necrosis factor-xcex1 (TNF) or cachectin, interleukin-1 (IL-1), IL-6, gamma-interferon (IFN), and prostaglandins (PGs) (e.g., PGE2).
Anorexia, with progressive depletion of body stores leading to the cachectic state, is observed in 50% of cancer-bearing patients. Different mechanisms proposed to explain the pathogenesis of anorexia include: (i) increased production of cytokines such as TNF and IL-1, and (ii) increased serotoninergic activity within the central nervous system secondary to enhanced availability to the brain of its precursor, tryptophan. Dickerson, J. W. T. et al., 1976, J. Neurochem 27: 1245-1247 have suggested that diets should be selected to keep the ratio of plasma tryptophan to the sum of neutral amino acids constant., Cangiano, C., et al., 1994, Anticancer Res. 14: 1451-1456 has also disclosed that a close relationship between plasma free tryptophan concentration and anoroxia in cancer patients supports the serotoninergic system activity in the pathogenesis of cancer anorexia.
Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, and lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant metastatic sites. Clinical data and molecular biologic studies indicate that cancer is a multi-step process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia causing metabolic effects such as cachexia.
Tumor cells differ from normal cells in their metabolism of fat in that tumor cells consume short-chain and medium-chain fatty acids poorly. For example, tumor-bearing mice fed a diet rich in medium-chain triglycerides had less weight loss with a marked reduction in tumor size compared with animals fed long-chain triglycerides. Moreover, there have been problems reported with the use of high levels of medium-chain triglycerides and use of structured lipids has been suggested in some total parenteral nutrition formulas. Moreover, these structured lipids do not provide the same benefits if administered enterally U.S. Pat. Nos. 4,906,664 and 5,081,105 disclose the use of certain structured lipids in the treatment of cancer. Preparations for enteral nourishment including varying ratios of xcfx89-6 to xcfx89-3 (2.1:1-3.0:1) have also been used in oncologic patients. However, these preparations used proportionately larger amounts of xcfx89-6 to xcfx89-3 fatty acids. Furthermore, these preparations did not include additional amounts of branched-chain amino acids and antioxidants as set forth in the present invention. The, use of the polyunsaturated fatty acid eicosapentaenoic acid is suggested for the treatment of cachexia by inhibiting lipolytic activity of lipolytic agents in body fluids and the activity of the enzyme guanidino-benzoatase. See Tsdale, M. J., and Beck, A., U.S. Pat. No. 5,457,130, issued Oct. 10, 1995; and Tisdale, et al. Cancer Research 50: 5022-5026 (August 1990). However, the product taught by Tisdale was in a solid dosage form, requiring an already ill patient to swallow 12-16 capsules per day. This method had serious drawbacks, including difficulty in swallowing, belching, and bad odor.
Thus, the prevention and/or treatment of cachexia and anorexia remain a frustrating problem. Both animal and human studies suggest that nutritional support is largely ineffective in repleting lean body mass in the cancer-bearing host. Randomized trials exploring the usefulness of total parenteral nutrition (TPN) support as an adjunct to cytotoxic antineoplastic therapy have, demonstrated little improvement in treatment results. See for example Brennan, M. F., and Burt, M. E., 1981, Cancer Treatment Reports 65 (Suppl. 5): 67-68. This, along with a clear demonstration that TPN can stimulate tumor growth in animals suggests the routine use of TPN in cancer treatment is not justified. Visner, D. L., 1981, Cancer Treatment Reports 65 (Suppl 5): 1-2.
Long chain fatty acid bio-pathways and physiological actions are discussed in U.S. Pat. No. 5,223,285 to DeMichele, et al., the entirely of which is incorporated herein by reference.
Also of interest is U.S. Pat. No. 5,444,054 to Garleb, et al. and a related U.S. Pat. No. 5,780,451 (allowed application Ser. No. 08/221,349). These documents describe compositions and methods useful in the treatment of ulcerative colitis. Such compositions include a protein source that can be intact or hydrolyzed proteins of high biological value (col. 21); an indigestible oligosaccharide such as fructooligosaccharide; and a lipid blend containing a relatively high proportion of eicosapentaenoic acid, which contributes to a relatively high xcfx89-3 to xcfx89-6 fatty acid ratio.
The methods of the invention generally comprise inhibiting metabolic and cytokine associated features of cachexia in an individual by administering a nutritional composition comprising an effective amount of xcfx89-3 fatty acids including, but not limited to alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid, alone or in combination with each other. The invention also relates to administering a nutritional composition comprising effective amounts of branched-chain amino acids, valine, leucine, isoleucine, or mixtures thereof, and with or without a reduced amount of tryptophan and hydroxytryptophan. The invention further provides a method of reducing oxidative damage and anti-cancer drug-induced immunosuppressive in a cancer patient by administering a nutritional composition comprising effective amounts of antioxidants including, but not limited to beta-carotene, vitamin C, vitamin E, selenium, or mixtures thereof.
In one aspect, the invention provides a method of preventing the onset of cachexia and/or anorexia, or treating existing cachexia and/or anorexia in a human comprising enterally administering to the human at least:
(a) an oil blend containing xcfx89-6 fatty acids and at least 450 mg of xcfx89-3 fatty acids, the weight ratio of xcfx89-6 fatty acids to xcfx89-3 fatty acids being from about 0.1 to about. 3.0; and
(b) a source of amino-nitrogen wherein 15% to 50% by weight of the amino acids of said source of amino-nitrogen are branched-chain amino acids; and
(c) an antioxidant component comprised of at least one nutrient selected from the group comprising beta-carotene, vitamin C, vitamin E, selenium, or mixtures thereof.
These components may be administered in a single composition or in separate vehicles. Preferably, about 15% to about 25% of the amino-nitrogen is provided by branched-chain amino acids; most preferably, about 20%. It is also preferred that the source of amino nitrogen provides tryptophan in an amount of less than about 5.0% by weight of the total amount of the amino acids of said source of amino-nitrogen; more preferably at a level of less than 3% by weight.
In another aspect, the invention provides a method of preventing the onset of anorexia or of treating existing anorexia in a human comprising administering to the human a nutritional composition comprising amino-nitrogen wherein about 5 to 25 grams of branched-chain amino acids selected from valine, leucine, isoleucine, or mixtures thereof are present in an amount from about 15% to about 50% by weight, preferably about 15-25%, of the total amount of amino-nitrogen present in said nutritional composition, and wherein tryptophan in an amount not greater than about 5.0% by weight of the total amount of amino acids is present in said composition and wherein xcfx89-6 and xcfx89-3 fatty acids are present at a weight ratio of from about 0.1 to about 3.0 and at least one antioxidant is present in the nutritional composition.
There is further disclosed a method for preventing immunosuppression in a human comprising administering to the human a liquid nutritional composition comprising:
(a) an oil blend containing xcfx89-6 and xcfx89-3 fatty acids, the weight ratio xcfx89-6 fatty acids to xcfx89-3 fatty acids being about from 0.1 to about 3.0; and
(b) an antioxidant component comprising about 2,500 to about 6,500 micrograms per liter beta-carotene, about 250 to about 1,000 milligrams per liter vitamin C, about 100 to about 500 I.U. per liter vitamin E, and about 75 to about 125 mcg per liter selenium.
There is also disclosed a method of enhancing the transport and efficacy of anticancer drugs in a human having a cancerous condition comprising administering to the human a nutritional composition comprising an oil blend containing xcfx89-6 and xcfx89-3 fatty acids, the weight ratio of total xcfx89-6 fatty acids to xcfx89-3 fatty acids being from about 0.1 to about 3.0.
In another aspect, the invention provides a liquid nutritional composition comprising per liter:
(a) at least 0.45 gm (450 mg) of xcfx89-3 fatty acids and wherein the weight ratio of xcfx89-6 fatty acids to xcfx89-3 fatty acids is from about 0.1 to about 3.0;
(b) at least 50 grams of a source of amino-nitrogen wherein 15 to 50% by weight of the amino-nitrogen is branched-chain amino acids and wherein tryptophan is present in an amount less than about 5.0% by weight of the total amino-nitrogen; and
(c) at least 1 gram of an antioxidant system comprising beta-carotene, vitamin C, vitamin E and selenium.
Generally, such compositions provide much higherlevels of the xcfx89-3 fatty. acids: preferably from about 1.0 gm to about 100 gm per liter; more preferably, from about 5.0 gm to about 10 gm per liter. Similarly, it is preferred that about 15-25% (typically about 20%) by weight of the source of amino-nitrogen is branched-chain amino acids.
The various methods according to the present invention may be accomplished by feeding a single composition that contains all the components of the invention (xcfx89-6 to xcfx89-3 oil, branched-chain amino acids and antioxidant system) or each component maybe fed individually. Further, these methods may be accomplished through the consumption of pills or capsules that contain the elements of the claimed invention. In one embodiment of the invention, a nutritional liquid formulation containing all the elements of the invention is contemplated except for the branched-chain amino acids which may be consumed in the form of a pill or tablet.
In yet another co-embodiment of the invention, a liquid nutritional product contains all the elements of the composition, wherein the branched-chain amino acids are dispersed within the liquid in the form of microcapsules. This administration of the branched-chain amino acids in the form of capsules, tablets, pills and/or microcapsules is advantageous since the organoleptic or taste properties of the amino acids are very objectionable.
In contrast to the prior art, the nutritional composition of the present invention is not restricted to correcting metabolism of just one nutrient class at a time, such as lipids or amino acids. Instead, a preferred nutritional multinutrient composition comprises a balanced formulation containing xcfx89-3 fatty acids, antioxidants, branched-chain, amino acids, and with or without a reduced level of tryptophan and 5-hydroxytryptophan. Such a composition can demonstrate strong inhibition of cachexia and anorexia associated with a variety of different cancers (disease states).
In yet another embodiment, the methods further optionally comprise administering the nutritional composition in combination with cancer chemotherapeutic agents, including but not limited to, 5-fluorouracil, mitomycin-C, adriamycin, chloroethyl nitrosoureas and methotrexate, to improve the transport of the drug into the target cancer cells and ultimately the efficacy of the anticancer agent.
The Examples presented below exemplify the use according to the methods of the invention of xcfx89-3 fatty acids, antioxidants, branched-chain amino acids with or without a reduced level of tryptophan in nutritional therapy of cachexia and anorexia in human patients suffering from different cancers, including, but not limited to, liver, breast, lung, prostate, gastrointestinal and pancreatic cancer.
xe2x80x9cCachexiaxe2x80x9d refers to a state of general ill health and malnutrition. It is often associated with and induced by malignant cancer, and is characterized by loss of appetite, loss of body mass, especially lean body mass, and muscle wasting.
xe2x80x9cAnorexiaxe2x80x9d refers simply to a loss of appetite, whether brought on by medical or psychological factors. Anorexia is often closely associated with, and generally contributes to, the cachexia seen in patients with advanced cancers. xe2x80x9cFatty acidsxe2x80x9d refer to a family of carboxylic acids having a hydrocarbon chain, generally from about 12 to 24 carbons long. When unsaturated (having a double bond) at least one point in the hydrocarbon chain, such fatty acids are designated by the position of the first double bond. xcfx89-3 fatty acids have a first double bond at the third carbon from the methyl end of the chain; and include, but are not limited to, xcex1-linolenic acid, stearidonic acid, eicosapentaenoic acid (xe2x80x9cEPAxe2x80x9d), docosapentaenoic acid and docosahexaenoic acid (xe2x80x9cDHAxe2x80x9d) and the like. xcfx89-6 fatty acids, have a first double bond at the sixth carbon from the methyl end of the chain; and include, but are not limited to, linoleic acid, xcex3-linolenic acid, arachidonic acid (xe2x80x9cAAxe2x80x9d), and the like. The ratio of xcfx89-6 fatty acids to xcfx89-3 fatty acids is simply the ratio of the total amounts (usually expressed as weight) of each type.
Branched-chain amino acids are amino acids that have a fork or branch in the side chain. These include primarily those having a carbon-carbon branch, i.e. valine, leucine and isoleucine; but may also include other types of branches.
xe2x80x9cNutritional matrixxe2x80x9d as used herein refers to a delivery vehicle that contains fats, amino nitrogen and carbohydrates and provides some or all of the nutritional support for a patient in the recommended daily amounts. Frequently a nutritional matrix will contain vitamins, minerals, trace minerals and the like to provide balanced nutrition.
xe2x80x9cCytokinesxe2x80x9d as used herein refer to the causative agents of cachexia in the cancer patient, produced by the individual in response to the presence of cancer, and include, but are not limited to, tumor necrosis factor (TNF) or cachectin, interleukin-1 (IL-1), IL-6 and gamma-interferon (IFN). TNF is produced by the macrophages in response to nonspecific stimuli including cancer, infection, trauma and stress. The mechanism of action in cancer cachexia involves an immune response to the tumor with the production of cytokines, which not only mediate tumor lysis but also the metabolic changes seen in cancer cachexia through specific TNF receptors and/or via the induction of other cytokine receptors.
While not intending the invention to be limited to any particular theory of operation, applicants describe below a probable mechanism. A mode of action of cytokines is mediated via interactions with receptors on the plasma membrane. This is typically defined as a signal transduction event. In general, a cytokine receptor consists of an extracellular domain, a transmembrane region spanning the phospholipid bilayer of the plasma membrane, and an intracellular domain having either enzymatic activity or binding other molecules, so that a signal is delivered inside the cell in response to the cytokine ligand interaction. The signal transduction mechanisms involve second messengers, including phospholipases, adenylate cyclase and cyclic, AMP, inositol phosphates, diacylglycerols and protein kinase C. More particularly, phospholipase A2 generates arachidonic acid, a precursor of dienoic prostaglandins, thromboxanes, prostacyclin and leukotrienes of the 4 series.
Cytokines such as TNF and IL-1 stimulate production of arachidonic acid metabolites which are important to their inflammatory and tissue damaging actions and are responsible for immunosuppression in general, and in exacerbating some preneoplastic conditions including metabolic changes seen in cancer cachexia.
The invention is based, in part, on a method of inhibiting signal transduction and cytokine activity using nutritional compositions comprising high levels of xcfx89-3 fatty acids, in particular, of the long chain (e.g. 20 or more carbons) xcfx89-3 fatty acids, eicosapentaenoic (EPA) and docosahexaenoic (DHA).
Since administration of EPA and DHA results in a reduction of arachidonic acid in membrane phospholipids, such an effect not only diminishes the supply of arachidonic acid as a precursor for the dienoic eicosanoids but also inhibits their production through competitive inhibition by EPA. The cyclooxygenase and lipoxygenase metabolites of EPA have attenuated activity. Furthermore, xcfx89-3 fatty acids, alpha-linolenic and stearidonic can be converted through elongation/desaturation to EPA; and similarly, DHA can be retroconverted to EPA. Thus, the methods of invention comprise methods of inhibiting cytokine activity (e.g., TNF, IL-1) and cancer cachexia by interfering with signal transduction at the receptor level and inhibiting arachidonic acid metabolism.
Incorporation of xcfx89-3 fatty acids in membrane phospholipids not only alters the activity of membrane-associated enzymes (e,g., phospholipase A2) but also alters the balance between constituent saturated and unsaturated fatty acids and regulation of membrane fluidity, facilitates the transport of anticancer drugs into, the cancer cells and thus enhances the efficacy of the drugs. Alberts, A. W., et al., 1978, Biochim. Biophys. Acta 509:239-250. In addition, the inhibition of arachidonic acid metabolism results in prevention and/or reversal of immunosuppression by reducing the production of prostaglandins and leukotrienes (PGE2 and LTB4), which are immunosuppressive.
The invention also provides a method of reducing the concentration of brain tryptophan and serotonin to prevent or inhibit premature satiety and cancer cachexia and/or anorexia in a cancer patient in whom the prevention and treatment of cancer anorexia is desired by administering effective amounts of branched-chain amino acids, valine, leucine, isoleucine, or mixtures thereof, and with or without a reduced amount of tryptophan.
The methods and compositions of the invention provide a method of manipulating the concentration of brain tryptophan by: (i) increasing the branched-chain amino acids, which provide competition for tryptophan for penetration across the blood-brain barrier; and (ii) reduced levels of tryptophan and 5-hydroxytryptophan in relation to branched-chain amino acids in the nutritional composition of the invention. Such an intervention can increase appetite and thus prevent and/or treat cancer anorexia.
The methods and compositions of the invention also provide a method of reducing the risk or progression of certain symptoms of cancer, such as cancer cachexia and anorexia by administering antioxidant nutrients including, but not limited to, beta-carotene, vitamin C, vitamin E, selenium, or mixtures thereof. Epidemiological evidence indicates that a combination of beta-carotene, vitamin E and selenium can effect a reduction in cancer risk in some populations. Blot, N. J. et al., 1993, J. Natl Cancer Inst. 85: 1483-1492. Furthermore, vitamin E is added to satisfy any additional requirements as a result of a higher intake of xcfx89-3 polyunsaturated fatty acids. By the administration of the antioxidant nutrients of the invention to cancer patients having cachexia and whose immune system has been depressed on account of chemotherapy and/or oxidative burden, improvements in the nutritional status, as well as prevention and treatment of immunosuppression and cachexia can be achieved.
Nutritional support in the cancer patient can be categorized as (i) supportive, in which nutrition support is instituted to prevent nutrition deterioration in the adequately nourished patent or to rehabilitate the depleted patient before definitive therapy; (ii) adjunctive, in which nutrition support plays an integral role in the therapeutic plan; and (iii) definitive, in which aggressive nutrition support is required for the patient""s existence. The routes for providing nutrition support include an oral diet, tube feeding and peripheral or total parenteral nutrition. The preferred embodiment for nutritional methods and compositions of the invention is by the oral route.
An alternate to oral feeding is tube feeding by means of nasogastric, nasoduodenal, esophagostomy, gastrostomy, or jejunostomy tubes.
A typical nutritional composition useful in the method of this invention will have a caloric distribution as follows: about 12 to 24% (target 21%) from a source of amino-nitrogen, about 40 to 65% (target 61%) from carbohydrate and about 10 to 35% (target 18%) from fat. More particularly, the oil blend may comprise approximately 30% of xcfx89-3 fatty acids, preferably largely consisting of eicosapentaenoic acid and docosahexaenoic acid. Dietary oils used in the preparation of the nutritional composition generally contain xcfx89-3 fatty acids in the triglyceride form and include, but are not limited to canola, medium chain triglycerides, fish, soybean, soy lecithin, corn, safflower, sunflower, high-oleic sunflower, high-oleic safflower, olive, borage, black currant, evening primrose and flaxseed oil. Table 1 sets forth both preferred amounts and ranges for an oil blend useful in the invention. Specifically, the weight ratio of xcfx89-6 fatty acids to xcfx89-3 fatty acids in the lipid blend according to the invention is about 0.1 to 3.0. The daily delivery of xcfx89-3 fatty acids should be at least 450 mg and may vary depending on body weight, sex, age and medical condition of the individual. As mentioned, higher levels are desired for adult human consumption: for example, from about 0.5 to 50 gm daily, more preferably from about 2.5 to 5 gm daily.
Table 2 presents the fatty acid profile of an exemplary oil blend useful in the present invention. The weight ratio of the total xcfx89-6 fatty acids to the total xcfx89-3 fatty acids in this embodiment is 0.26 to 1 which is within the claimed range for this invention.
Table 3 (above) sets forth selected characteristics of an oil blend useful in the method of this invention. However, it will be realized that the characteristics may vary among other formulas useful for this invention, depending on the specific oils added and the ratios in which they are used.
An amino acid profile for a nutritional composition useful in the invention is presented in Table 4.
The total amount of branched-chain amino acids (xe2x80x9cBCAAxe2x80x9d) useful in the present invention is about 15-50 g/100 g protein (i.e. percent), preferably about 15-25 g/100 g. Thus, an 8 oz container of the nutritional composition would contain up to about 8 g BCAAs per 16 grams of total protein. The daily delivery of BCAAs is about 5-26 g. In order to deliver such a high amount of the BCAAs, and because the BCAAs impart an unpleasant taste, the nutritional composition may be accompanied by 1-3 gelatin capsules containing BCAAs to provide the additional amount required above the inherent amount present in the liquid product. The preferred BCAAs are, but are not limited to, leucine, isoleucine and valine, and are predominantly bitter in taste. Therefore, administering the additional BCAAs in encapsulated form avoids taste problems which are encountered with the use of quantities greater than 20 g/100 g protein of BCAAs in the liquid product. The micro encapsulated BCAAs may also be mixed with taste masking compounds including, but not limited to, polyphosphates, cyclodextrin (a cyclic glucose oligomer) and Thaumatin (a proteinaceous intense sweetener).
A representative antioxidant profile useful in the method of the invention is presented in Table 5 with range values and a preferred embodiment.
The overall nutrient profile of this example is set forth in Table 6. In a specific embodiment of this invention, the nutritional product provides at least 100% of the U.S. RDA for vitamins and minerals in 1184 mL (five 8 fluid ounce servings), which would provide 1184 kcal per day.
If used as a sole source of nutrition, and assuming a 2000 kcal diet, between 8 and 9 servings (237 mL; 8 fluid ounces) of this illustrative formulation would be required. However, as seen from example IV below, there is benefit derived from supplementation with as few as two servings per day. Thus a minimum daily amount of long chain xcfx89-3 fatty acids is preferably about 3 grams, calculated as (1.06 g EPA+0.46 g DHA) times 2 8 oz servings. Of course, if more servings are consumed to provide additional calories, more xcfx89-3 fatty acids will be administered, up to a practical maximum of about 14 grams per day (about 9 servings at same fatty acid levels); Levels of the fatty acids, antioxidants and/or source of amino nitrogen on a per liter basis are not crucial, except to the extent that a reasonable volume of fluid should supply the recommended daily amounts consistent with the invention. Determination of a reasonable volume is easily within the ambit of those skilled in the art especially in view of the specific guidance found in the examples.